Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC)

Status: 
Completed
Clinicaltrials.gov identifier: 
NCT03288545
Sponsor: 
Seagen Inc., Astellas Pharma, Merck & Co., Inc.
Enrollment: 
149
Study Design: 
Cohort K of this trial included untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer were randomized 1 : 1 to either EV monotherapy (1.25 mg/kg) on days 1 and 8 or in combination with pembrolizumab (200 mg) on day 1 of 3-week cycles.
Rationale: 
The current first-line standard of care for locally advanced or metastatic urothelial carcinoma is cisplatin-based combination chemotherapy. However, cisplatin-ineligibility limits first-line treatment options. This trial explores the efficacy of enfortumab vedotin (EV) in the first-line setting for cisplatin-ineligible patients with and without pembrolizumab as they both have shown benefit independently in the second-line and later settings. EV is an antibody-drug conjugate. It is a nectin-4-directed antibody and microtubule inhibitor conjugate. Pembrolizumab is an anti-PD-1 monoclonal antibody approved in the treatment of urothelial cancer after chemotherapy or in platinum ineligible patients who express PDL-1.
Endpoints: 
The primary endpoint was confirmed objective response rate (ORR) per RECIST v1.1 by BICR (blinded independent central review). Secondary endpoints included duration of response (DOR) and safety (treatment-related adverse events, TRAEs). There were no formal statistical comparisons between treatment arms.
Comments: 
There are limited options for first line therapy for cisplatin-ineligible metastatic urothelial cancer patients. This trial not only reaffirms the benefit of EV monotherapy but also demonstrates safety and efficacy with the combination of EV and pembrolizumab, that could become a new standard of care.
Results: 
A total of 149 patients, 73 in the EV arm and 76 in the combination arm, were enrolled and treated. Confirmed ORR for the EV arm was 45.2% (95% CI: 33.5-57.3) and median DOR was 13.2 months (95% CI: 6.1-16.0). Confirmed ORR for the combination arm was 64.5% (95% CI: 52.7-75.1) and median DOR was not yet reached. TRAEs occurred more commonly in the combination arm compared to the monotherapy arm and included: skin reactions (67.1% vs. 45.2%, respectively) and peripheral neuropathy (60.5% vs. 54.8%, respectively). Lesser TRAEs include ocular disorders and hyperglycemia.